Regulation of protein synthesis
A composition and method for inhibiting proliferation of a tumor cell compared to a non-tumor cell. Also described are methods of screening for a composition that inhibits cap-dependent translation compared to cap-independent translation of proteins.
1. A method of inhibiting preferentially cap-dependent protein synthesis in a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with a compound of the formula
wherein
R 1 is a hydrazone thiazole moiety of the structure
R 2 is hydrogen, hydroxyl or a nitro group present in one, two or three locations on the ring to which it is attached;
R 3 is a group individually present in one, two or three locations on the ring, wherein the group may be halo, hydrogen, conjugated or unconjugated aryl or heteroaryl, a alicyclic or polycyclic group, or R 3 , taken with the ring to which it is attached, forms a conjugated ring structure;
R 4 is hydrogen, carboxyl, a lower alkyl ester or carbonyl, in which case the dotted bond is present;
R 5 is N, in which case the dotted bond is present, or NH; and
R 6 is NH.
2. The method of claim 1 , wherein said compound is
3. The method of claim 1 , wherein said compound displaces a naturally-occurring 4E-BP-, or eIF4G-derived polypeptide, or a peptide containing the consensus YxxxxLΦ motif, where Φ stands for a hydrophobic residue and x is any amino acid.
4. The method of claim 1 , wherein said compound inhibits binding between eIF4E and full-length eIF4G.
5. The method of claim 1 , wherein said compound binds at or adjacent to V69, W73, Y76, Ser82, Ser83, L131, L135, or I138 of eIF4E.
6. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell in an individual in need of such inhibition, comprising administering to a patient a pharmaceutical composition comprising a compound of the formula
wherein
R 1 is a hydrazone thiazole moiety of the structure
R 2 is hydrogen, hydroxyl or a nitro group present in one, two or three locations on the ring to which it is attached;
R 3 is a group individually present in one, two or three locations on the ring, wherein the group may be halo, hydrogen, conjugated or unconjugated aryl or heteroaryl, a alicyclic or polycyclic group, or R 3 , taken with the ring to which it is attached, forms a conjugated ring structure;
R 4 is hydrogen, carboxyl, a lower alkyl ester or carbonyl, in which case the dotted bond is present;
R 5 is N, in which case the dotted bond is present, or NH; and
R 6 is NH.
7. The method of claim 6 , wherein said compound is
8. The method of claim 6 , wherein said patient is identified as having a tumor cell which comprises an increased level of a cap-dependent translation factor compared to the level in a normal non-tumor cell.
9. The method of claim 8 , wherein said patient is diagnosed as having a tumor cell which is characterized by an increased amount of a cap-dependent translation factor compared to the level in a normal non-tumor cell.
10. The method of claim 9 , wherein said translation factor is eIF4E.
11. The method of claim 6 , wherein said patient is identified as having a tumor.
12. The method of claim 6 , wherein said patient is identified as having a lymphoma or a neuroblastoma.
13. The method of claim 6 , wherein said patient is identified as having a bacterial or a viral infection.
14. A method of identifying a compound that preferentially inhibits proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell compared to a non cancerous cell of the same cell type, comprising contacting a cell with a compound of the formula
wherein
R 1 is a hydrazone thiazole moiety of the structure
R 2 is hydrogen, hydroxyl or a nitro group present in one, two or three locations on the ring to which it is attached;
R 3 is a group individually present in one, two or three locations on the ring, wherein the group may be halo, hydrogen, conjugated or unconjugated aryl or heteroaryl, a alicyclic or polycyclic group, or R 3 , taken with the ring to which it is attached, forms a conjugated ring structure;
R 4 is hydrogen, carboxyl, a lower alkyl ester or carbonyl, in which case the dotted bond is present;
R 5 is N, in which case the dotted bond is present, or NH; and
R 6 is NH
and detecting a reduction in the level of proliferation of the cancer cell in the presence of said compound compared to a non-cancer cell in the presence of said compound.
15. The method of claim 14 , wherein said tumor cell proliferation is at least 10% more compared to non-tumor cells.
16. The method of claim 14 , wherein said compound is a 2-thiazolyl hydrazone.
17. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with an isolated, pure, stable E isomer compound of the formula
wherein
R1 is a hydrazone thiazole moiety of the structure
R2 is hydrogen, hydroxyl, CN, CF 3 , CO 2 H, SO 3 H, PO 3 H 2 , SO 2 R, SO 2 NHR, SONH 2 , CONH 2 , CONHR, NHCOR, or a nitro group present in one, two or three locations on the ring to which it is attached and where R is an alkyl of 1-4 carbons or aryl;
R3 is a group individually present in one, two or three locations on the ring, wherein the group is halo, hydrogen, CN, CF 3 , CO 2 H, SO 3 H, PO 3 H 2 , SO 2 R, SO 2 NHR, SONH 2 , N=NR, CONH 2 , CONHR, NHCOR, conjugated or unconjugated aryl or heteroaryl, a alicyclic, heterocyclic or polycyclic group, or a conjugated ring structure when taken with the ring to which R 3 is attached, where R is an alkyl of 1-4 carbons or aryl;
R4 is hydrogen, lower hydroxyalkyl, carboxyl, a lower alkyl ester, tetrazole, SO 3 H or PO 3 H 2 ; or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 wherein the compound is an isolated, pure, stable E isomer compound of the formula
or a pharmaceutically acceptable salt thereof.
19. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with an isolated, pure, stable Z isomer compound of the formula
wherein
R1 is a hydrazone thiazole moiety of the structure
R2 is hydrogen, hydroxyl, CN, CF 3 , CO 2 H, SO 3 H, PO 3 H 2 , SO 2 R, SO 2 NHR, SONH 2 , CONH 2 , CONHR, NHCOR, or a nitro group present in one, two or three locations on the ring to which it is attached and where R is an alkyl of 1-4 carbons or aryl;
R3 is a group individually present in one, two or three locations on the ring, wherein the group is halo, hydrogen, CN, CF 3 , CO 2 H, SO 3 H, PO 3 H 2 , SO 2 R, SO 2 NHR, SONH 2 , N=NR, CONH 2 , CONHR, NHCOR, conjugated or unconjugated aryl or heteroaryl, a alicyclic, heterocyclic or polycyclic group, or a conjugated ring structure when taken with the ring to which R 3 is attached, where R is an alkyl of 1-4 carbons or aryl;
R4 is hydrogen, lower hydroxyalkyl, carboxyl, a lower alkyl ester, tetrazole, SO 3 H or PO 3 H 2 ; or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 wherein the compound is an isolated, pure, stable Z isomer compound of the formula
or a pharmaceutically acceptable salt thereof.
21. A method of inhibiting preferentially cap-dependent protein synthesis in a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with an isolated, pure, stable E isomer compound of the formula
or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 wherein the compound is in a pharmaceutical composition including a pharmaceutically acceptable carrier.
23. A method of inhibiting preferentially cap-dependent protein synthesis in a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with an-isolated, pure, stable Z isomer compound of the formula
or a pharmaceutically acceptable salt thereof.
24. The method of claim 23 wherein the compound is in a pharmaceutical composition including a pharmaceutically acceptable carrier.
25. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with a compound of the formula
wherein
R 1 is a hydrazone thiazole moiety of the structure
R 2 is hydrogen, hydroxyl or a nitro group present in one, two or three locations on the ring to which it is attached;
R 3 is a group individually present in one, two or three locations on the ring, wherein the group may be halo, hydrogen, conjugated or unconjugated aryl or heteroaryl, a alicyclic or polycyclic group, or R 3 , taken with the ring to which it is attached, forms a conjugated ring structure, e.g., a naphthalene ring;
R 4 is hydrogen, carboxyl, a lower alkyl ester or carbonyl, in which case the dotted bond is present;
R 5 is N, in which case the dotted bond is present, NH; and
R 6 is NH.
26. The method of claim 25 , wherein said compound is
27. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with an isolated, pure, stable E isomer compound of the formula
or a pharmaceutically acceptable salt thereof.
28. The method of claim 25 wherein the compound is in a pharmaceutical composition including a pharmaceutically acceptable carrier.
29. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with an-isolated, pure, stable Z isomer compound of the formula
or a pharmaceutically acceptable salt thereof.
30. The method of claim 1 wherein the conjugated ring structure is a naphthalene ring.
31. The method of claim 1 wherein the lower alkyl ester is
32. The method of claim 6 wherein the conjugated ring structure is a naphthalene ring.
33. The method of claim 6 wherein the lower alkyl ester is
34. The method of claim 14 wherein the conjugated ring structure is a naphthalene ring.
35. The method of claim 14 wherein the lower alkyl ester is
36. The method of claim 25 wherein the conjugated ring structure is a naphthalene ring.
37. The method of claim 25 wherein the lower alkyl ester is
38. A method of inhibiting preferentially cap-dependent protein synthesis in a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with a compound of the formula
or a pharmaceutically acceptable salt thereof.
39. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell in an individual in need of such inhibition, comprising administering to a patient a pharmaceutical composition comprising a compound of the formula
or a pharmaceutically acceptable salt thereof.
40. A method of inhibiting proliferation of a breast cancer cell, a prostate cancer cell, a lung cancer cell, a pancreatic cancer cell or a colon cancer cell, comprising contacting said cell with a compound of the formula
or a pharmaceutically acceptable salt thereof.